Valsartan is a commonly-available specific angiotensin II antagonist which acts on the AT1 receptor subtype. It is used in the treatment of hypertension, diabetes related hypertension, heart attack, post myocardial infarction and lung cancer. The structure of valsartan is as shown below:

Chemically, valsartan is known as N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl]methyl]-L-valine, has a molecular weight of 435.5 and the chemical formula C24H29N5O3. Valsartan is a white to practically white fine powder. It is soluble in ethanol, methanol and is slightly soluble in water.
Biologically, valsartan is a non-peptide and is capable of oral administration. Tablets of the compound with strength 40 mg, 80 mg, 160 mg and 320 mg are available.
Valsartan was first disclosed in U.S. Pat. No. 5,399,578, hereinafter referred to as '578. The patent describes a procedure for the preparation of valsartan as depicted in Scheme 1.

The process disclosed in the scheme 1 has the following disadvantages.    a) The unavoidable use of toxic tributyl azide in the formation of the tetrazole ring. Reaction in the presence of tributyl azide leads to the formation of hydrogen azide which is explosive in nature. Moreover, tributyl azide is a hazardous chemical in itself. Use of the same on an industrial scale necessitates professional handling at all times. This leads to an overall increase in the handling and production costs.    b) The intermediates formed in the disclosed Scheme I are oily in nature. Their crystallization is an enormous task which often requires repeated steps of crystallization. The yield and the quality of the end product obtained by using the stated procedure in accordance with Scheme I is therefore greatly compromised. Moreover the crystallizations and re-crystallizations procedures carried out on an industrial scale, make the process laborious and time consuming.
The '578 patent discloses an alternate process for the preparation of valsartan, wherein 4-bromomethyl-2′-(1-triphenylmethyltetrazol-5-yl)biphenyl is reacted with (L)-valine benzyl ester hydrochloride in DMF to obtain N-[(2′-tetrazolylbiphenyl-4-yl)methyl]-(L)-valine benzyl ester. This is then acylated with valeryl chloride. The benzyl ester group is then removed by hydrogenation to obtain valsartan. The reaction procedure is depicted in Scheme 2.

A disadvantage of the process according to Scheme 2 is that all intermediates obtained are oily in nature and their crystallization from this oily form is very difficult. This in turn affects both the yield and purity of the final product. Re-crystallization procedures become mandatory for the improvement of the yield. These are necessarily time consuming and further add to the net cost of the product. The purity of the end product is greatly compromised owing to the presence of un-crystallized intermediates.
The other disadvantage of the '578 patent is that, one can not reproduce the result by following the processes as disclosed in Example 55. The procedure is limited to the method of preparation of benzyl ester only. Further, lack of data on weighed quantities of the reactants and incomplete disclosure of synthesis steps limit the scope of the patent's teachings for the preparation of valsartan. By following the analogous examples, valsartan was obtained with poor purity and had to be re-crystallized several times to achieve the desired purity. Many intermediates are isolated by flash chromatography. This requires an increased usage of raw materials, solvents, labor, energy and time. Eventually it adds to the net cost of the end product.
WO 2004/101534 (hereinafter referred to as '1534) focuses on a process for the preparation of a valsartan where an intermediate of formula (IV) is converted to its hydrochloride salt as shown in Scheme 3.

The hydrochloride salt is then converted to valsartan (I) by reacting with valeryl chloride (V) and removing protective groups.
The process according to Scheme 3 has the following disadvantages.    a) The preparation of the hydrochloride salt must be carried out at exact pH and temperature conditions only. Even a slight temperature rise or variation in pH leads to the detritylation of the intermediate resulting in undesired impurities. The purity of the final product is thus always a difficult consideration during the formation of the hydrochloride salt of this intermediate.    b) It is a known fact that, the trityl group is highly unstable in an acidic environment. Patent application '1534 teaches that the reaction must be carried out at a highly acidic pH of 1, to convert the intermediate IV into its hydrochloride salt. There are strong chances that detritylation of the protecting trityl group may occur at such adverse pH conditions. In case such detritylation does occur, the final yield of valsartan is inadvertently reduced. Thus, in effect, a process step which is introduced to ease the crystallization procedure may de-protect a desired group in the intermediate compound affecting the net purity. Also the possibility of production of some new intermediates owing to the occurrence of detritylation cannot be avoided. This may in turn result in undesired side reactions in the subsequent steps.    c) The hydrochloride salt (IV—HCl) is further purified using inflammable and hazardous solvents like hexane and has a purity of 92% only.
Indian application no 421/CHENP/2005 (herein after referred to as IN '421) discloses another process for preparation of valsartan and an intermediate IIa thereof. The process according to IN '421 does not use an azide moiety for the formation of tetrazole compound. The process according to the IN '421 application is shown in Scheme 4.

A disadvantage of the above process is that it requires strict maintenance of pH and the process is quite lengthy.
U.S. Pat. No. 7,199,144 (US '144) discloses yet another process for the preparation of valsartan and precursors thereof. The method of preparation of valsartan is the same as disclosed in '578, but it provides alternative methods to remove residual solvent, particularly ethyl acetate (of which the permissible limit is less than 5000 ppm) from the final product. The following methods used:    1) Crude, valsartan is triturated with water (about 4 liter/kg of crude product) at a temperature of around 24-40 degrees.    2) By performing a solvent exchange by contacting the solvate with humid gas in a fluidized bed apparatus at around 30 degrees.    3) By harsh drying which is carried out by maintaining the valsartan at a temperature of about 5 to about 60 degree C. under pressure of less than about 30 mmHg.
However, the disadvantages associated with the '578 patent, remain with the US '144 process, for example production of oily intermediates, unavoidable use of toxic azides and the like.
US 20060281801 discloses yet another process for the preparation of valsartan. It provides a purification method for the removal of the organotin impurity from benzyl valsartan. The purification process includes:    (1) Crystallization of benzyl valsartan from a ternary solvent mixture comprising a hydrophilic organic solvent, a non-polar organic solvent, and water    (2) Crystallization from a polar aprotic solvent, a non-polar organic solvent, or mixtures thereof. Preferably, the second crystallization solvent is a binary solvent mixture comprising a polar aprotic solvent and a non-polar organic solvent.
As the process requires a method for recrystallization, it is very time consuming and the purity of the end product is highly questionable as the intermediates are oily.
The processes disclosed in the prior art are therefore cumbersome and not feasible industrially.
Hence, there is a need to develop a more efficient and economical synthetic route suitable for industrial scale-up.